Compositions for a once day treatment of cyclooxygenase-2 mediated diseases

ABSTRACT

This application relates to a method of treating a disease susceptible to treatment with a non-steroidal anti-inflammatory drug by administering to a patient once daily an effective amount of 3-phenyl-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone.

RELATED APPLICATION DATA

This is a National phase U.S. application of PCT/US97/08041, filed May13, 1997, which claims priority from U.S. Provisional Application60/017,878, filed May 17, 1996 and British application GB 9612063.9,filed Jun. 10, 1996.

This application is also a continuation of U.S. Ser. No. 08/851,756,filed May 6, 1997 now abandoned, which claims priority from U.S.Provisional application 60/017,878, filed May 17, 1996.

BACKGROUND OF THE INVENTION

This invention relates to pharmaceutical compositions for the treatmentof cyclooxygenase-2 mediated diseases, mehe use of a compound in themanufacture of a medicament.

In particular, this invention relates to a pharmaceutical compositionfor the treatment of cyclooxygenase-2 mediated diseases, saidcomposition being suitable for once a day administration, saidcomposition comprising a cyclooxygenase-2 inhibiting characterized byhigh potency for the inhibition of cyclooxygenase-2, a long half-lifeand a high degree of specificity for inhibiting cyclooxygenase-2 inpreference to cyclooxygenase-1. Such a compound is exemplified by3-phenyl-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, ##STR1##

Non-steroidal anti-inflammatory agents are normally administered 2 to 4times daily. The relatively short half-life of most non-steroidalanti-inflammatory agents means that once a day administration isimpractical and even twice a day administration is unusual. Therelatively large doses needed to achieve once a day treatment ofconventional non-steroidal anti-inflammatory agents would also lead toside effects so that there is a general understanding that once a dayadministration is unlikely to be achievable.

Surprisingly a compound has been identified which can be employed on aonce a day basis and which will not produce an unacceptable level ofside effects on such a regimen, and in particular will not cause anunacceptable level of gastric side effects.

U.S. Pat. No. 5,474,995, issued Dec. 12, 1995, WO 95/00501, publishedJan. 5, 1995 and WO 95/18799, published Jul. 13, 1995, disclose3,4-di-substituted furanones and derivatives thereof as potent,selective inhibitors of cyclooxygenase-2. We have found that3-phenyl-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, possesses asurprising combination of attributes that make it possible to formulateand use the composition in a surprising manner. Not only is the compoundpotent, safe and effective at modest oral dosages of 5 to 125 mg ofagent per day, but in addition this active agent possesses a half-lifein humans of sufficient length that a single oral dose of 5 to 125 mg ofagent per day will provide effective safe anti-inflammatory treatmentover a 24 hour period. Such active agents are particularly useful in thetreatment of chronic indications, including arthritis, pain, Alzheimer'sdisease and the like.

SUMMARY OF THE INVENTION

This invention is directed to a pharmaceutical composition for thetreatment of cyclooxygenase-2 mediated diseases, said composition beingsuitable for once a day oral administration, said composition comprisinga cyclooxygenase-2 inhibiting compound characterized by high potency forthe inhibition of cyclooxygenase-2, a long half-life and a high degreeof specificity for inhibiting cyclooxygenase-2 in preference tocyclooxygenase-1. Such a compound is exemplified by3-phenyl-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone.

In one aspect, this invention is directed to a pharmaceuticalcomposition for the treatment of cyclooxygenase-2 mediated diseases, aidcomposition being suitable for once a day oral administration, saidcomposition comprising 5 to 125 mgs of the above mentioned compound.

The invention is also directed to a method of treating cyclooxygenase-2mediated diseases comprising the once a day oral administration of 5 to125 mgs of the above mentioned compound.

The invention is also directed to the use the above mentioned compoundin the manufacture of a medicament containing 5 to 125 mgs of saidcompound for once a day administration for the treatment ofcyclooxygenase-2 mediated diseases.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, this invention is directed to a pharmaceuticalcomposition for the treatment of cyclooxygenase-2 mediated diseases,said composition being suitable for once a day administration, saidcomposition comprising a cyclooxygenase-2 inhibitor characterized byhigh potency for the inhibition of cyclooxygenase-2, a long half-lifeand a high degree of specificity for inhibiting cyclooxygenase-2 inpreference to cyclooxygenase-1.

In one genus, of this embodiment, this invention is directed to apharmaceutical composition for the treatment of cyclooxygenase-2mediated diseases, said composition being suitable for once a day oraladministration, said composition comprising a cyclooxygenase-2inhibiting compound characterized by.

(a) high potency for the inhibition of cyclooxygenase-2 as measured bythe ability of a single therapeutic dose of said compound to providerelief from the post-operative pain accompanying the removal of two orthree molars, said relief being statistically equal to or greater thanthat obtained with a single dose of 400 mg of ibuprofen;

(b) a half-life or 9 or more hours, preferably 15 hours or more and morepreferably 18 hours or more; and

(c) a high degree of specificity for inhibiting cyclooxygenase-2 inpreference to cyclooxygenase-1 as measured by the statistical failure ofa therapeutic dose of said compound to inhibit the generation of serumthromboxane B2.

One such compound is 3-phenyl-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, ##STR2##

As will be appreciated by those of skill in the art, this invention isdirected only to compounds which act by inhibiting cyclooxygenase-2.Thus, the characterization requirements set out above cannot be said tobe met unless the mode of action of the compound is as an inhibitor ofcyclooxygenase-2. For example, a central nervous system agent mayrelieve pain with a potency equal to or greater than ibuprofen, yet notmeet the requirements set out above, because it does not act oncyclooxygenase-2. See Inflamm. Res. 45:68-74 (1996) encorporated hereinby reference, which discloses an (LPS)-challenge test for clinicalidentification and evaluation of cyclooxygenase-2 inhibition, andthromboxane B2 levels in the blood. Equivalent tests may also be used.Compounds of the instant invention are not hepatotoxic at therapeuticdoses. Moreover, compounds of the instant invention demonstrate an ED₃₀in the rat paw edema assay of 0.4 mg/kg or less when measured asdisclosed in WO 95/00501 and a selectivity for the inhibition of COX-2over COX-1 of 50:1 or more measured as disclosed on WO 95/00501.

In one embodiment, this invention is directed to a pharmaceuticalcomposition for the treatment of cyclooxygenase-2 mediated diseases,said composition being suitable for once a day oral administration, saidcomposition comprising a 5 to 125 mg of3-phenyl-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, and apharmaceutical carrier therefor.

3-Phenyl-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, its utility andmethods of making them are disclosed in U.S. Pat. No. 5,474,995, issuedDec. 12, 1995, WO 95/00501, published Jan. 5, 1995 and WO 95/18799,published Jul. 13, 1995, which are hereby incorporated by reference.

As discussed in U.S. Pat. No. 5,474,995 compounds, including3-phenyl-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, are useful for therelief of pain, fever and inflammation of a variety of conditionsincluding rheumatic fever, symptoms associated with influenza or otherviral infections, common cold, low back and neck pain, dysmenorrhea,headache, toothache, sprains and strains, myositis, neuralgia,synovitis, arthritis, including rheumatoid arthritis, degenerative jointdiseases (osteoarthritis), gout and ankylosing spondylitis, bursitis,burns, injuries following surgical and dental procedures. In addition,such a compound may inhibit cellular neoplastic transformations andmetastic tumor growth and hence can be used in the treatment of cancer.It is also useful for the treatment of dementia including pre-senile andsenile dementia, and in particular, dementia associated with AlzheimerDisease (ie Alzheimer's dementia).

The compound will also inhibit prostanoid-induced smooth musclecontraction by preventing the synthesis of contractile prostanoids andhence may be of use in the treatment of dysmenorrhea, premature laborand asthma.

By virtue of its high cyclooxygenase-2 (COX-2) inhibitory activityand/or its selectivity for inhibiting COX-2 over cyclooxygenase-1(COX-1) the specified compound is also useful as an alternative toconventional non-steroidal antiinflammatory drugs (NSAID'S) particularlywhere such NSAIDS may be contra-indicated such as in patients withpeptic ulcers, gastritis, regional enteritis, ulcerative colitis,diverticulitis or with a recurrent history of gastrointestinal lesions;GI bleeding, coagulation disorders including anemia such ashypoprothrombinemia, haemophilia or other bleeding problems (includingthose relating to reduced or impaired platelet function); kidney disease(eg impaired renal function); those prior to surgery or takinganticoagulants; and those susceptible to NSAID induced asthma.

For the treatment of any of these cyclooxygenase mediated diseases thecompound may be administered orally or by intravenous infusion.

As indicated above, pharmaceutical compositions for treating COX-2mediated diseases as defined may optionally include one or moreingredients as listed above.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. The compositionsare intended for oral use and may be prepared according to any methodknown to the art for the manufacture of pharmaceutical compositions andsuch compositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example, magnesium stearate, stearic acid or talc.

Other suitable formulations are set forth in U.S. Pat. No. 5,474,995.However, in view of the unique set of properties possessed by3-phenyl-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, including longhalf-life, low solubility, high potency, de minimis gastrointestinal(GI) side effects, we have found the following oral formulations to beof particular value:

Rapidisc®--In view of the above mentioned characteristics,3-phenyl-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone is particularlywell suited for a rapid dissolving sublingual formulation. For example,due to the lack of GI side-effects, the agent need not be take with alarge amount of water. Suitable Rapidisc® formulations and methods ofmaking same are disclosed in U.S. Pat. Nos. 4,305,502, 4,371,516,4,470,202, 4,758,598, 4,754,597, 5,046,618 and 5,188,882, all of whichare hereby incorporated by reference.

As mentioned in the Background section, we have found3-phenyl-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone to possess asurprising combination of attributes. Not only are these active agentspotent safe and effective at modest oral dosages of 5 to 125 mg of agentper day, but in addition these active agents possess a half-life inhumans of sufficient length that a single oral dose of 5 to 125 mg ofactive agent per day will provide effective safe anti-inflammatorytreatment over a 24 hour period. Such agents are particularly useful inthe treatment of chronic indications, such as rheumatoid and osteoarthritis as well as Alzheimer's Disease.

Oral and intravenous dosage levels for agent3-phenyl-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone are of the order offrom about 5 to 125 per patient per day.

The amount of active agent that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration of humans may containfrom 5 to 125 mg of agent compounded with an appropriate and convenientamount of carrier material which may vary from about 5 to about 95percent of the total composition. Dosage unit forms may typicallycontain 5, 10, 12.5, 20, 25, 50, 75, 100 or 125 mg of active agent.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination and the type and severity of theparticular disease undergoing therapy. For many patients, a dosage rangeof 5 to 50 or 12.5 to 25 or 25 to 75 mg per day is preferred.

For long term therapy, such as in the treatment of chronic diseasesincluding rheumatoid arthritis, osteoarthritis or Alzheimer disease, adosage of 5 to 50 or 12.5 to 25 mg per day is preferred. Moreparticularly, for the treatment of osteoarthritis, a dosage of 5, 10,12.5, 25 or 50 mg per day is preferred, whereas for the treatment ofrheumatoid arthritis, 10, 12.5, 25 or 50 mg per day is preferred. Forthe treatment of non-chronic indications such as headache orpost-operative swelling and pain, 10, 12.5, 25 or 50 mg per day ispreferred.

Accordingly, in one aspect the invention is directed to a unit dose oralform which comprises from 5 to 50 or 5 to 22.5 mg of the cyclooxygenaseinhibitor, for example, 12.5 or 20 mg or 12.5 to 25.

In another aspect this invention is directed to a pharmaceuticalcomposition for the treatment of cyclooxygenase-2 mediated diseases,said composition suitable for once a day oral administration, saidcomposition comprising a 5 to 50 or 25 to 75 mg of3-phenyl-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, and apharmaceutical carried therefor.

Within this aspect there is a first genus of compositions comprising 5to 50 mg of 3-phenyl-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone.

Within this aspect there is a second genus of compositions comprising 10to 50 mg of 3-phenyl-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone.

Within this genus there is a class of compositions comprising 5 to 22.5mg of 3-phenyl-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone.

Within this genus there is a class of compositions comprising 12.5 to 25mg of 3-phenyl-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone.

Within this genus there is a class of compositions comprising 5, 10,12.5, 25 or 50 mg of3-phenyl-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone.

EXAMPLE 1

    ______________________________________                                        Wet granulated tablet composition                                               Amount per tablet  Ingredient                                               ______________________________________                                        25       mg          COX-2 Inhibitor                                            79.7 mg Microcrystalline cellulose                                            79.7 mg Lactose monohydrate                                                   6 mg Hydroxypropyl cellulose                                                  8 mg Croscarmellose sodium                                                    0.6 mg Iron oxide                                                             1 mg Magnesium stearate                                                     ______________________________________                                    

Tablet dose strengths of between 5 and 125 mg can be accomodated byvarying total tablet weight, and the ratio of the first threeingredients. Generally it is preferable to maintain a 1:1 ratio formicrocrystalline cellulose: lactose monohydrate.

EXAMPLE 1a

    ______________________________________                                        Wet granulated tablet composition                                               Amount per tablet  Ingredient                                               ______________________________________                                        12.5     mg          COX-2 Inhibitor                                            86 mg Microcrystalline cellulose                                              86 mg Lactose monohydrate                                                     6 mg Hydroxypropyl cellulose                                                  8 mg Croscarmellose sodium                                                    0.6 mg Iron oxide                                                             1 mg Magnesium stearate                                                     ______________________________________                                    

EXAMPLE 1b

    ______________________________________                                        Wet granulated tablet composition                                               Amount per tablet  Ingredient                                               ______________________________________                                        10       mg          COX-2 Inhibitor                                            87.2 mg Microcrystalline cellulose                                            87.2 mg Lactose monohydrate                                                   6 mg Hydroxypropyl cellulose                                                  8 mg Croscarmellose sodium                                                    0.6 mg Iron oxide                                                             1 mg Magnesium stearate                                                     ______________________________________                                    

EXAMPLE 1c

    ______________________________________                                        Wet granulated tablet composition                                               Amount per tablet  Ingredient                                               ______________________________________                                        5        mg          COX-2 Inhibitor                                            89.7 mg Microcrystalline cellulose                                            89.7 mg Lactose monohydrate                                                   6 mg Hydroxypropyl cellulose                                                  8 mg Croscarmellose sodium                                                    0.6 mg Iron oxide                                                             1 mg Magnesium stearate                                                     ______________________________________                                    

EXAMPLE

    ______________________________________                                        Directly compressed tablet composition                                          Amount per tablet  Ingredient                                               ______________________________________                                        25       mg          COX-2 Inhibitor                                            106.9 mg Microcrystalline cellulose                                           106.9 mg Lactose anhydrate                                                    7.5 mg Crosmellose sodium                                                     3.7 mg Magnesium stearate                                                   ______________________________________                                    

Tablet dose strengths of between 5 and 125 mg can be accomodated byvarying total tablet weight, and the ratio of the first threeingredients. Generally it is preferable to maintain a 1:1 ratio formicrocrystalline cellulose: lactose monohydrate.

EXAMPLE 2a

    ______________________________________                                        Directly compressed tablet composition                                          Amount per tablet  Ingredient                                               ______________________________________                                        12.5     mg          COX-2 Inhibitor                                            113.2 mg Microcrystalline cellulose                                           113.2 mg Lactose anhydrate                                                    7.5 mg Croscarmellose sodium                                                  3.7 mg Magnesium stearate                                                   ______________________________________                                    

EXAMPLE 2b

    ______________________________________                                        Directly compressed tablet composition                                          Amount per tablet  Ingredient                                               ______________________________________                                        10       mg          COX-2 Inhibitor                                            42.5 mg Microcrystalline cellulose                                            42.5 mg Lactose anhydrate                                                     4 mg Croscarmellose sodium                                                    1 mg Magnesium stearate                                                     ______________________________________                                    

EXAMPLE 2c

    ______________________________________                                        Directly compressed tablet composition                                          Amount per tablet  Ingredient                                               ______________________________________                                        5        mg          COX-2 Inhibitor                                            45 mg Microcrystalline cellulose                                              45 mg Lactose anhydrate                                                       4 mg Croscarmellose sodium                                                    1 mg Magnesium stearate                                                     ______________________________________                                    

EXAMPLE

    ______________________________________                                        Hard gelatin capsule composition                                                Amount per capsule Ingredient                                               ______________________________________                                        25       mg          COX-2 Inhibitor                                            37 mg Microcrystalline cellulose                                              37 mg Lactose anhydrate                                                       1 mg Magnesium stearate                                                       1 capsule Hard gelatin capsule                                              ______________________________________                                    

Capsule dose strengths of between 1 and 50 mg can be accomodated byvarying total fill weight, and the ratio of the first three ingredients.Generally it is preferable to maintain a 1:1 ratio for microcrystallinecellulose: lactose monohydrate.

EXAMPLE

    ______________________________________                                        Oral solution                                                                   Amount per 5 mL dose   Ingredient                                           ______________________________________                                        50         mg            COX-2 Inhibitor                                      to 5 mL with Polyethylene oxide 400                                           ______________________________________                                    

Solution dose strengths of between 1 and 50 mg/5 mL can be accomodatedby varying the ratio of the two ingredients.

EXAMPLE

    ______________________________________                                        Oral suspension                                                                 Amount per 5 mL dose                                                                           Ingredient                                                 ______________________________________                                        101     mg         COX-2 Inhibitor                                              150 mg Polyvinylpyrrolidone                                                   2.5 mg Poly oxyethylene sorbitan monolaurate                                  10 mg Benzoic acid                                                          to 5 mL with sorbitol solution (70%)                                          ______________________________________                                    

Suspension dose strengths of between 1 and 50 mg/5 ml can be accomodatedby varying the ratio of the first two ingredients.

EXAMPLE

    ______________________________________                                        Intravenous infusion                                                            Amount per 200 mL dose                                                                             Ingredient                                             ______________________________________                                        1          mg          COX-2 inhibitor                                          0.2 mg Polyethylene oxide 400                                                 1.8 mg Sodium chloride                                                        to 200 mL Purified water                                                    ______________________________________                                    

STARTING MATERIALS PREPARATION 1

3-(Phenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Step 1: 2-Bromo-1-(4-(methylsulfonyl)phenyl)ethanone

A solution of 197 g of 4-(methylthio)acetophenone (ref: J. Am. Chem.Soc., 1952, 74, p. 5475) in 700 mL of MeOH and 3500 mL of CH₂ Cl₂ wasadded 881 g of MMPP over a period of 30 min. After 3 h at r.t. thereaction mixture was filtered and the filtrate was washed with 2 L ofsaturated aqueous solution of NaHCO₃ and 1 L of brine. The aqueous phasewas further extracted with 2 L of CH₂ Cl₂. The combined extracts weredried over Na₂ SO₄ concentrated to give 240 g of4-(methylsulfonyl)acetophenone as a white solid.

To a cooled (-5° C.) solution of 174 g of4-(methylsulfonyl)-acetophenone in 2.5 L of CHCl₃ was added 20 mg ofAlCl₃, followed by a solution of 40 mL of Br₂ in 300 mL CHCl3. Thereaction mixture was then treated with 1.5 L of H₂ O and the CHCl₃ wasseparated. The aqueous layer was extracted with 1 L of EtOAc. Thecombined organic extracts were dried over Na₂ SO₄ and concentrated. Thecrude product was recystallized from 50/50 EtOAc/hexane to give 210 g ofthe title compound as a white solid.

Step 2: 3-(Phenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

To a solution of phenylacetic acid (27.4 g, 201 mmol) and2-bromo-1-(4-(methylsulfonyl)phenyl)ethanone (Step 1) (60 g, 216 mmol,1.075 eq.) in acetonitrile (630 mL) at 25° C. was added slowly Et₃ N(30.8 mL, 1.1 eq.). The mixture was stirred for 20 min. at r.t. and thencooled in an ice bath. DBU (60.1 mL, 3 eq.) was slowly added. Afterstirring for 20 min. in the ice bath, the reaction was complete and themixture was acidified with 1N HCl (color changed from dark brown toyellow). Then 2.4 L of ice and H₂ O were added, the mixture was stirredfor a few minutes, and the precipitate was filtered and rinsed with H₂O, giving 64 g of crude wet product. The solid was dissolved in 750 mLof CH₂ Cl₂, dried over MgSO₄, filtered and 300 g of silica gel was addedto the filtrate. The solvent was evaporated to near dryness (silica gela bit sticky), the residue was applied on top of a silica gel plug in asintered glass funnel and eluted with 10% EtOAc/CH₂ Cl₂, giving afterevaporation of the solvent and swishing in EtOAc, 36.6 g (58%) of thetitle compound.

Analysis: Calculated for C₁₇ H₁₄ O₄ S: C, 64.95; H, 4.49; S, 10.20Found: C, 64.63; H, 4.65; S, 10.44

PREPARATION 2

3-(Phenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Into a 20 mL glass ampule are added 1 g of2-(4-(methylsulfonyl)phenyl)phenylacetylene (J. Am. Chem. Soc., 1971,93, p. 2979), 20 mg of Rh₄ (CO)₁₂, 1.5 g of Et₃ N, 10 mL of THF, and 1mL of H₂ O under a nitrogen atmosphere, and the ampule is placed in a100-mL stainless steel autoclave. The reaction system is flushed threetimes with CO then charged at r.t. to an initial CO pressure of 100 atm.The reaction is carried out at 100° C. for 5 h. The solution is thendiluted with 50 mL of benzene and washed with brine and 1N HCl. Thebenzene solution is dried over Na₂ SO₄, and concentrated. The crudeproducts are separated by column chromatography on silica gel, elutingwith 2:1 EtOAc/hexane to give the title compound and its regioisomer.

PREPARATION 3

3-(Phenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Step 1: 2-trimethylsilyloxy-4-(4-(methylthio)phenyl)-3,4-dihydrofuran

To a solution of 3.86 g (19 mmol) of 4-bromothioanisole in 90 mL of Et₂O cooled at -78° C., is added 22 mL of a 1.7 M solution of t-BuLi inpentane (38 mmol) dropwise. The reaction mixture is stirred for 15 minat -78° C. and 3.8 g of CuI is added and the reaction mixture is allowedto warm to -40° C. over a period of 30 min. A solution of 1.7 g of2(5H)-furanone in 10 mL of THF is added. After stirring for 1 h, 2 mL offreshly distilled TMSCl is added dropwise. The reaction mixture is thentreated with 2 mL of Et₃ N and 50 mL of sat. NaHCO₃, and extracted with100 mL of Et₂ O. The Et₂ O layer is dried over Na₂ SO₄ and concentratedto give the crude title compound which is used for the next step withoutfurther purification.

Step 2: 4-(4-(Methylthio)phenyl)-2-(5H)-furanone

To a solution of 4 g of Pd(OAc)₂ in 100 mL of acetonitrile is addeddropwise the crude product from Step 1(5 g) under nitrogen at r.t. After10 h at r.t., the mixture is concentrated under reduced pressure and theresidue is purified by flash chromatography on silica gel eluted with2:1 hexane/EtOAc to give the title compound.

Step 3: 3-Iodo-4-(4-(methylthio)phenyl)-2-(5H)-furanone

To a solution of 3 g of the product of Step 2 in 30 mL of pyridine isadded 8.7 g of I₂. The mixture is stirred for 24 h and then diluted with200 mlL of Et₂ O, washed with 100 mL of 5N HCl and 50 mL of 5N Na₂ S₂O₃. The Et₂ O layer is dried over Na₂ SO₄ and concentrated to give thetitle compound.

Step 4: 3-(Phenyl)-4-(4-(methylthio)phenyl)-2-(5H)-furanone

A mixture of 4 g of the product of Step 3, 3.7 g of PhB(OH)₂, 0.4 g ofPh₃ As, 0.4 g of PdCl₂ (PhCN)₂ in 100 mL of benzene and 15 mL of 2N NaOHis refluxed for 6 h. After cooling to r.t., Et₂ O (200 mL) is added tothe reaction mixture and the mixture is washed with 100 mL of saturatedNaHCO₃. The organic layer is dried over MgSO₄ and concentrated. Theresidue is purified by flash chromatography on silica gel eluted with4:1 hexane/EtOAc to give the title compound.

Step 5: 3-(Phenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

To a solution of 3 g of the product of Step 4 in 80 mL of 10:1 CH₂ Cl₂/MeOH is added 5.5 g of MMPP. The reaction mixture is stirred at r.t.for 2 h and then diluted with 100 mL of 1:1 hexane/EtOAc. Afterfiltration and concentration, the residue is purified by flashchromatography eluted with 2:1 EtOAc/hexane to give the title product.

ABBREVIATIONS

DBU=1,8-diazabicyclo[5.4.0]undec-7-ene

Et₃ N=triethylamine

MMPP=magnesium monoperoxyphthalate

THF=tetrahydrofuran

TMSCl=trimethylsilyl chloride

What is claimed is:
 1. A method of treating a disease susceptible totreatment with an non-steroidal anti-inflammatory agentcomprising:administration orally once a day to a human patient in needof such treatment 12.5 or 25 or 50 mg of3-phenyl-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone.
 2. A methodaccording to claim 1 for the treatment of non-chronic headache, pain orswelling.
 3. A method according to claim 1 for the treatment ofosteoarthritis.
 4. A method according to claim 1 for the treatment ofrheumatoid arthritis.
 5. A method according to claim 1 for the treatmentof pain.
 6. A method according to claim 1 for the treatment of fever. 7.A method according to claim 1 for the treatment of dysmenorrhea.
 8. Amethod according to claim 1 for the treatment of Alzheimer's disease.